Preparation of calcium acetylsalicylate



Patented June 4, 1935 a 7 umrso STAT-ES PATENT OFFICE 2,003,374 tPREPARATION OF CALCIUM ACETYL- SALICYLATE William H. Lawrence, Jr.,Marblehead, Mass, as-

signor to Lee Laboratories, Incorporated, Cambridge, Mass, a corporationof Delaware NoDrawing. Application July 21, 1932,

Serial No. 623,813

7 BClaims. (01. 260-107) This invention relates to improvements in Ithas been the theory'that the instability of methods of preparing thecalcium salt of acetylcalcium aspirinhas been due to the presence ofsalicylic acid. The invention also contemplates the alkaline-earth,calcium, in the salt because a more stable calcium acetylsalicylate thanhas it is thought that the calcium in the presence of heretofore beenprepared for commercial use. moisture accelerates the hydrolysis of thesalt 5 The desirability ofprocuring aspirin in a more and causes; theconsequent liberation of acetic assimilable form has long beenrecognized by and salicylic acids. "Calcium aspirin as heretothe medicalprofession. Aspirin itselfis an infore prepared has been; hygroscopicand numersoluble acid and it frequently causes gastric disous effortshave been made to compound the salt 10 turbances in the stomach while,due to its insoluwith agents adapted to minimize or reduce its 10bility, it is not so readily transmitted to the inhygroscopicity.Again,- in attempts to reduce testine as it might otherwise be; itsdesirable the instability of the salt, dry preparations of antipyreticand analgesic actions takes place aspirin and compounds of metalsadapted to after it has been attacked and absorbed by the form solublesalts of aspirin in the presence of a alkaline media in the duodenalregion of the di- .solvent, have been compounded, but these have 15gestive system. V H not found commercial application tov any con-Calcium acetylsalicylate or calcium aspirin is siderable extent. awater-soluble salt of aspirin having. all the de- The reaction involvedin producing Calcium sirable therapeutic properties of. aspirin with thepirinv is theoretically quite simple. Acetylsaliadded advantage of moreready assimilation by cylic acid is combined with a calcium compound 20the digestive tract. This is due 'toits ready soluwhich has usually analkaline reaction, to form tion in aqueous media. Forupwards of twentydirectly the calcium salt of the acid. Prior art years efiorts have beenmade to supply this subproposals comprise reacting a compound constance,but hitherto the calcium aspirin offered taining the radica ofacetylsalicylic acid, Such as to the trade has been of small commercialor the acid itself or an alkaline salt thereof, with a 25 medicinalvalue because it has always been in a calcium compound, such as a saltor a calcium very unstable form, so that by the time it reachedalcoholate. The tendency of calcium asp t0 the consumer it was composedlargelyof calcium yd y e in t presence Water has Caused salicylate and/or salicylic acid, and contained y prior investigators t v d t presenceof but little calcium acetylsalicylate. 1 I water or at least reduce theamount emp y a 30 The necessity that calcium aspirin be reasonmuch aspossible. It has thus been proposed to ably stable so that it willwithstand the exigeneffect these reactions by mixing Solutions o thecies of climate and storage on the part of the reagen sin yl 0methyla100h01r Since alkali user, it will be appreciated whenconsideration is Promotes hydrolysis in e Presence 0f WatGIU'thB givento the effects of the decomposition of the use of calcium hydroxide asthe source of the'cal- 35 salt. When aspirin and calcium aspirindecomcium is pr l although attempts have been 7 pose they form aceticacid and salicylic acid. ad t c b aspirin and Calcium-hydroxideSalicylic acid is insoluble in ;the'aqueous acid in the p c of a OrganicSolvent aq media of the mouth and stomach, it is further- Solutions ofcommon salt or calcium chloride.

40 more very acid and a relatively strong irritant Another proposalconsists in'reacting a solution 40 of the walls of the stomach, and thusin the preof aspirin in w t w either a d calcium c e maturedecomposition of aspirin or calcium as- 1 11 an aqueous Solution of h 1pirin a more irritating agent than aspirin itself centrating the mixtureand permitting crystalis released. V 4 lization to take place assistedif desired-by the Aspirin is reasonably stable, but calcium asadditionof an organic precipitating agent. It 45 pirin, as made heretofore, isexceedingly unhas also been proposed ,to add dry calcium-carstable anddoes not, withstand ordinary storage bonate to a suspension ofaspirin inwater in the conditions for any considerable length of time. proportionsof 1.2 and after filtering to precipi- The requirements of commercialand medicinal tate the calcium aspirin by the addition of ethylpractices are such that for a drug of this nature or methyl alco to bereally useful it must be capable of ordi- I These prior attempts havefailed entirely to nary storage without material decomposition forproduce a product which is acceptable to the upwards of six monthsorayear.) The calcium medical profession, or a product whichdoes notaspirin as prepared by former methods failed undergo spontaneousdecomposition under ordimeet thee r qu nt l nary conditions of storagein arelatively short 6.5

each other.

length of time. These desiderata are achieved in accordance with thisinvention which is based upon the observation that the successfulproduction of stable calciumaspirin is dependent upon various operatingfactors to which prior investigators paid little or no attention.

I have found that calcium aspirin, to be stable, should not contain anyconsiderable quantity of iron compounds; it should have not more thanand it'is more efficacious in use due to its greater resistance todecomposing influences of the upper part of the gastro-intestinal tract.

A product of this nature is securedby the careful practice of myimproved method of manufacture, in which purity of the reagents, removalof decomposition products and accidental impurities, temperature controland freedom of the reagents to react with each other, play importantparts.

The preferred reagents are substantially pure acetylsalicylic acid andprecipitated chalf. Chalk is preferred to calcium hydroxide owing to thestrong alkaline reaction of the latter tending to promote hydrolysis andthus-decrease the yield. These reagents should contain as little iron,magnesium and other like impurities as possible. The removal ofdecomposition products and other undesirable impurities is effected bysubjecting the product to the action of an agent adapted to dissolve orabsorb the impurities and any excess water. Methyl alcohol or methanolis peculiarly adapted for this purpose and I have found that byrepeatedly subjecting calcium aspirin to washings by or digestions inthis solvent, a stable product is obtainable. Finally, in order thatgood yields may be secured it is necessary that the reagents haveadequate freedom to react with To this end water is usedas the liquidmedium assisted by continuous agitation. Yields, from 60% to over of thetheoretical yield, of astable product assaying at 99.5% purity(calculated as CmHnOs Ca. 3.5 Aq.) are obtained.

Practical embodiments of the invention will now be disclosed in detail,by way of example.

Example 1.500 grams of finely powdered ace tylsalicylic acid and 160grams of calcium carbonate (precipitated chalk), are intimately mixedand 3000 cc. of water is added The mixture is stirred for 15 minutes oruntil the reaction is completed, which is indicated by the cessation ofthe liberation of carbon dioxide. The temperature is desirablymaintained below 20 C. by any suitable cooling means. The mass isallowed to settle until the supernatant liquor is almost clear; thisusually takes about 5 minutes, and the mixture is then filtered toremove unreacted material. V This part of the process is carried out asquickly as possible so as to minimize any tendency of the calciumaspirin to hydrolyze in the solution. The filtrate is cooled to about 18C.

and 1 to lt volumes of 97% methanol, or pure wood alcohol is added. Thiscauses the calcium aspirin to precipitate and the mass is then filtendto remove as thoroughly as possible the temperature.

mother liquor. The residue of calcium aspirin is then suspended in aquantity of methanol equivalent to the volume previously used as aprecipitant, and it is allowed there to stand for an hour or more withoccasional or continuous agitation. The mass is again filtered, thefiltrate being employed for the precipitation of calcium aspirin in alater batch. After the filtering of the first wash liquor, the calciumaspirin is again suspended in another quantity of methanol of anequivalent volume. This constitutes the second wash and ,it is carriedout in same way as the first wash. The filtrate is employed as a firstwash in a later batch and this filtrate in turn is used, as is thefiltrate of the first wash, for the precipitation of more calciumaspirin. Fresh alcohol is used as a new wash in a later batch and thewashes are carried out in series. After the second wash the calciumaspirin is dried in a suitable manner, as bypassing dry warm air overit, the temperature not being allowed to rise to such an extent as todecompose the aspirin; pref erably the temperature is not permitted torise above 50 C., but should be high enough toavoid deposition of watervapor, and the drying is completed when there is no longer an odor ofmethanol. 7

Example 2.-As an alternative method of purifying the crude calciumaspirin which has men first precipitated with methanol the filter massof the first precipitated calcium aspirin may be dissolved in sufiicientcold water at about 10 C., filtered if necessary, from any slightinsoluble material, and then precipitated with 1 volumes of methanol.filtered, washed with a little to 1 97% methanol and dried carefully ata suitable It may be found desirable to give the re-precipitated calciumaspirin one further digestion with 95% to 97% methanol to partlydehydrate as in Example 1.

Example 3.-The reaction of acetylsalicylic acid and calcium carbonate iscarried out as in Example 1 and the water filtered off aftercompletionof the reaction. The sediment is washed with about 250 cc. ofwater. In precipitating, 1 volumes of methanol are added to the clearfiltrate which is stirred until the calcium salt of the acetylsalicylicacid begins to separate out, and isthen allowed to stand until theseparation of the calcium-salt is complete, the temperature beingmaintained below 20 C. The salt is then filtered and washed thoroughlywith methanol. After being sucked free from mother liquor, it is spreadon a filter paper and air-dried. 7 Example 4."I'he reaction is carriedout in accordance with Example 1, the calcium aspirin being precipitatedwith 1 volumes of methanol, and is, after filtering removed from thefilter and suspended in 2500 cc. methanol. After standing several hours,the calcium aspirin is removed by filtration and again suspended in 2500cc. of fresh methanol for the same length of time. The calcium aspirinis then filtered off and dried until no odor of methanol remains.

Example 5.- The procedure is the same as for Example 4, except thatthree washes of 2500 cc.

of methanol each are used instead of two-washes. Different temperaturesmay be employed in the washings, the first wash being for 2 hours at 20C., the second for 1 hour at 40 C., and the third for 1 hour at 70 C.

Example 6.-The reaction of acctylsalicylic acid and chalk is carried outin accordance with Example 3, up to the washing of the sediment withabout 250 cc. of water. The volume of clear filthe method for theprecipitation of the calcium been added. After 1 volume (3700 cc.) hasbeen added, an additional half volume of methanol is added (1850 cc.).The mixture is then allowed to stand three hours for completecrystallization,

the temperature being maintained between and C.,this beingconsideredimportant. The mixture is then filtered, washed and dried asset forth inthe preceding examples. A yield of 515 grams of calcium aspirincontaining 3 molecules of water, and containing85.8%' of anhydrouscalciuinacetylsalicylate has been obtained. This is equal to atheoretical yield of 79.4%.

The crystals'so obtained were more granular than those obtained by theprevious experiments.

They have an average lengthof 0.25 mm., a width of 0.112 mm. or larger.

A preferred form of procedure for the crystallization of my calciumaspirin, and one that lends itself best to a practical method is asfollows: The aqueous solution of the calcium aspirin, after filtrationfrom the-excess 'of calcium carbonate and other insoluble substances, ischilled to 5 C. if it has not already been brought to this temperature.This solution is placed in a vessel capable of being maintained at afigure close to this temperature, and provided with slow means ofagitation.

The required amount of methanol is then run in slowly and preferablyduring a period of about two hours. The agitation is so conducted as tobarely keep the crystals of calcium aspirin in slow movement as theyareformed. This combination of slow movement, slow addition of methanol,and low temperature, provides at once a large yield and relatively largecrystals. Furthermore, the crystals are relatively thick for theirlength. This relationship of thickness to length provides an easyflowing crystalline powder.

It will be appreciated that these examples are susceptible of variationin respect of the various time.

operating factors employed. A slight excess of pure calcium carbonate(usually about 10%) over the theoretical combining weight withacetylsalicylic acid is generally employed. Both the calcium carbonateand the acetylsalicylic acid are in a finely powdered state and theyshould both pass through a screen of 200 meshes to the linear inch. Whenthe chalk and the aspirin are intimately mixed, the rate of reaction onmoistening depends upon the fineness of the powders used.

The finer the powder, particularly of the aspirin, he greater is therate of reaction, while efficient stirring after the addition of thewater enables the reaction to go to completion in a very short A smalleramount of water than the volume mentioned in the examples tends todecrease the yield since then much of the chalk and aspirin would beleft in an uncombined state, or possibly calcium acetylsalicylate isthrown out of solution as formed. The reaction itself should bemaintained at a temperature of not more than 20 C. During the reactioncarbon dioxide is given 01f and. a heavy foam containing chalk andaspirin is formed. This is broken by rapid stirring, and as aprecaution,a small amount of ether may be added to break the foam. The reactionusually requires about minutes for completion, while 5 minutesisgenerally sufilcient .to permit the mass to settle before filteringoff the turbid supernatant liquor. While larger quantities ofmethyl'alcohol or methanol than those specified in the examples, maybeemployed, I have found that the best results aresecured with the use of1 volumes, as stated.

The apparatus employed should be free.v from iron, and the reaction isdesirably effected in glass or enamel-lined vessels. It the process iscarried out in accordance with these directions the product will notcontain more than 10 parts of iron per million, and it is'not difficultto reduce the iron content to less than 5 parts per million. The waterof crystallization and any hygroscopic water similarly should not exceed3 /2 molecules, and there will not be any measurable amount ofundesirable impurities such as acetates, salicylates, salicylic or.other free acids. The addition of a few drops of a 10% solutionof'ferric chloride to 300 or 400 milligrams of salt dissolved in 15 tocc. of water will result in the precipitation of ferric acetylsalicylateas a light buff colored precipitate, and the absence of a purple colorwill show that the salt has not decomposed into salicylates.

TheIcalcium aspirin obtained in accordance with this process ismore'stable than that produced by prior methods and is capable ofordinary storage without material decomposition for upwards of sixmonths or a year. It may be compounded into tablet form for medicinaluse by incorporation of the usual excipients, such as talc and starch.Furthermore, these tablets or pills may be provided with a binderconsisting of a hard fatty substance such as one of the higher fattyacids, a glyceride of a higher fatty acid or a hydrogenated vegetableoil. Stearic acid, and hydrogenated cotton seed oil are examples ofsuitable binders and coating compositions which may be used to protecttablets of my calcium aspirin from excessive moisture during storage,and from the action of the upper partof the gastro-intestinal tractduring administration of them as a medicine.

I claim:

l. A process of preparing calcium acetylsalicylate which comprisesintimately mixing precipitated chalk and finely powdered aspirin, addingwater and stirring to complete the reaction at a temperature of not morethat 20 C., filtering the supernatant liquor obtained on permitting themass to settle, digesting the filtrate with a methanol-containingliquid, filtering 01f the precipitated calcium acetylsalicylate anddigesting the residue with an agent which is a non-solvent iii forcalcium acetylsalicylate but which is adapted digesting said liquor withone and one-half volumes of methanol, filtering ofi the precipitatedcalcium aspirin and digesting it with methanol until the iron content isnot; more than 10 parts per million, and finally drying at a temperatureof not more than 50 C.

3. A processof preparing calcium vacetylsalicylate which comprisesintimately mixing precipitated chalk and finely poweredacetylsalicylate, adding water to the mixture in anamount equal to aboutsix times the total weight of theacetylsalicylate,"permitting thereaction to proceed to completion at a temperature of not more than 20vC., permitting the mixture to settle, filtering the supernatant liquor,digesting the filtrate with methanol, filtering off the precipitatedcalcium acetylsalioylate, washing the residue with meth anol, repeatingsaid washing with ,fresh methanol, and finally drying at a temperatureor not over 50 C.

4. A process ofpreparing calcium acetylsalicylate which comprisesintimately mixing precipi tated chalk and finely powderedacetylsalicylate, adding water to the mixture in an amount equal toabout six times thetotal weight of the acetylsalicylate, permitting thereactionflto proceed to completion at a temperature of not more than 20C. permitting the mixture to settle, filtering the supernatant liquor,cooling the filtrate to about. 5 to 10 ,C., digesting the filtrate withmethanol by adding amounts of methanol equal to" one-tenth thevolume ofthe filtrate while slowly agitating the resulting mixture until thetotal amount of methanol added is equal to the volume of the originalfiltrate, adding a further amount of methanol equal to one-half thevolume of the original filtrate, permitting the mixture to stand forseveral hours and maintaining the temperature thereof at between 5 and10 C., filtering oil the crystals or calcium acetylsalicylateprecipitated in the filtrate, and washing and drying said crystals.

5. A process of preparing calcium acetylsalicylate whichcomprises'intimately mixing precipitated chalk and finely powderedacetylsalicylate,

adding water to the mixture in an amount equal to about six times thetotal weight of the acetylsalicylate, permitting the reaction to proceedto completion at'atemperature'of not more than 20 (3., permittingthe'mixture to settle, filtering the supernatant liquor, digesting thefiltrate with methanol, filtering off the precipitated calciumacetylsalicylate, redissolving the filtered calcium acetylsalicylate ina small volume of water, reprecipitating the calcium acetylsalicylatewith methanol, filtering off the resulting precipitate, washing theprecipitate with methanol, and drying at a low temperature.

6. A process of stabilizing crude calcium acetylsalicylate whichcomprises dissolving the same in a sufiicient quantity of cold water atabout 10 C., digesting the resulting solution with1 volumes of methanol,filtering out the resulting precipitated crystals of calciumacetylsalicylate, washing the crystals with methanol, and drying thecrystals at a temperature of not over 50 C.

WILLIAM H. LAWRENCE, JR.

